tbuckley/cabot-search huggingface dataset:
Integrated analysis of pivotal biomarker, immune cell infiltration, and therapeutic drugs for LSM1-mutated in breast cancer.
Authors: Yen-Dun Tony Tzeng, Jim Jinn-Chyuan Sheu, Chia-Jung Li
Journal: Journal of Clinical Oncology (2022)

e13011 Background: The discovery of early diagnosis and prognostic markers for breast cancer can significantly improve survival and reduce mortality. LSM1 is known to be involved in the general process of mRNA degradation in complexes containing LSm subunits, but the molecular and biological functions in breast cancer remain unclear. Methods: In the present study, we investigated the expression profiles, prognostic roles, and genetic alterations of LSM1 in patients with breast cancer through several public databases, containing Oncomine and Gene Expression Profiling Interactive Analysis, Human Protein Atlas, Kaplan–Meier plotter and cBioPortal. Then, we constructed the protein-protein interaction networks of LSM1 proteins and their interactors by using the String database and Cytoscape software. In addition, we performed the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichmente. Finally, we explored the mechanisms underlying LSM1 involvement in BRCA by using gene set enrichment analysis. Results: We found that functional LSM1 inactivation caused by mutations and profound deletions predicted poor prognosis in BRCA patients. LSM1 was highly expressed in both BRCA tissues and cells compared to normal breast tissues/cells. High LSM1 expression is associated with poorer overall survival and disease-free survival. The association between LSM1 and immune infiltration of breast cancer was assessed by TIMER and CIBERSORT algorithms. LSM1 showed a strong correlation with various immune marker sets. Most importantly, pharmacogenetic analysis of BRCA cell lines revealed that LSM1 inactivation was associated with increased sensitivity to refametinib, and trametinib. However, both drugs could mimic the effects of LSM1 inhibition and their drug sensitivity was associated with MEK molecules. Therefore, we investigated the clinical application of LSM1 to provide a basis for sensitive diagnosis, prognosis and targeted treatment of breast cancer. Conclusions: In brief, our finding may contribute to increasing currently limited prognostic biomarkers and treatment options for breast cancer.
Clinicopathological characteristics of high-risk multiple myeloma in Hispanic versus non-Hispanic patients in central California.
Authors: Andrew Hwang, Jason Doornenbal, Daniel Park, Inderpreet Bal, Mohammed SANI Bukari, Yueqi Yan, Haifaa Abdulhaq
Journal: Journal of Clinical Oncology (2022)

8056 Background: Roughly 37% of Multiple Myeloma (MM) patients in the U.S. are non-white minorities. Advanced stage at diagnosis and specific cytogenetic abnormalities are associated with high-risk disease and poor prognosis. Few studies evaluated these risk factors in ethnic minorities. To further investigate, we analyzed ethnic variations in characteristics and outcomes of high-risk MM patients who were treated at our institution in Fresno, CA (49.6% Hispanic population). Methods: Patients diagnosed with high-risk MM at Community Medical Centers from 1-1-2011 to 12-31-2020 were included. High risk was defined by Mayo Clinic mSMART 3.0 classification. Demographic and disease-relevant information were collected. Cytogenetics, R ISS stage, 1st line treatment (doublet vs triplet), and treatment response (IMWG response criteria) were evaluated. Hispanic and non Hispanic comparisons were made by Fisher’s exact test where appropriate. Progression Free Survival (PFS) and Overall Survival (OS) were evaluated by Kaplan-Meier estimates and compared via log-rank test. Univariate cox proportional hazard model for survival was used to examine the association of variables with mortality risk after 1st line therapy. Results: 147 MM patients were screened. 42 high risk patients were identified: 11 (26%) Hispanic, 31 (74%) non Hispanic (22 white, 8 African American, 1 East Indian). Median age at diagnosis was 65. 26 (61%) were females. 25 (59%) were R ISS stage 3. Hispanic vs non Hispanic median income was $46119 vs $65080 (p=0.035). 6 Hispanics had Medi-Cal insurance vs 2 non-Hispanics (54.6% vs 6.5%, p=0.003). More Hispanics had Lambda light chain disease (73% vs 26%; p=0.01). 13 non Hispanics had del 17p vs 0 Hispanics (p=0.009). 40/42 patients (95%) received triplet therapy. 4 Hispanics received ASCT vs 9 non Hispanics (40% vs 33.3%, p=0.716). Hispanics and non Hispanics did not have significantly different treatment responses per IMWG criteria (p=0.799). No significant difference in PFS was seen between Hispanics and non Hispanics (805 vs 793 days; p=0.089); OS was better in Hispanics (1062 days vs 453 days; p=0.008). Per univariate cox proportional Hazard model, female sex (HR 4.34) and age (HR 1.05) were associated with higher mortality while Hispanic ethnicity was associated with lower mortality (HR 0.19). Conclusions: Hispanic and non Hispanic high risk MM patients differed significantly in median income, insurance, and del 17p incidence. These did not translate to a difference in 1st line therapy or treatment response. OS in our study is higher in Hispanic high-risk MM patients compared to other ethnicities and warrants further investigation. [Table: see text]
Total neoadjuvant chemoradiation combined with neoadjuvant PD-1 blockade for patients with pMMR, high-risk, and locally advanced middle to low rectal cancer.
Authors: Aiwen WU, Yingjie Li, Dengbo Ji, Li Zhang, Xiaoyan Zhang, Yong Cai, Yangzi Zhang, Yunfeng Yao, Lin Wang, Jiahua Leng, Tiancheng Zhan, Ying-Shi Sun, Zhongwu Li, Xiaoli Cui, Haitao Luo
Journal: Journal of Clinical Oncology (2022)

3611 Background: Total neoadjuvant therapy (TNT) with chemotherapy and chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal cancer patients, especially for those with high risk factors. And the effects of immune checkpoint inhibitors (ICIs) on rectal cancer with defect mismatch repair (dMMR) have been demonstrated. However, the efficacy of TNT combined with PD-1 blockage for rectal cancer patients with proficient mismatch repair (pMMR) is unknown. The purpose of this study is to evaluate the clinical safety and efficacy of neoadjuvant PD-1 blockade combined with TNT in locally advanced rectal cancer with pMMR. Methods: We designed a prospective, single-arm, phase II study on stage II and III dMMR rectal cancer with high risk factors. Patients received neoadjuvant POC regimen (PD-1 inhibitor, camrelizumab, also called SHR01210, 200mg d1, Oxaliplatin 130mg/m2 d1 and Capecitabine 1250mg/m2 bid1-14, q3wks) for three cycles, then with long course chemoradiation (IMRT, 1.8Gy/f*25f). If there were no disease progression occurs, patients would be treated with another two cycles of CapeOx. The primary endpoint was pathological complete response rate (pCR rate), and the secondary outcome include adverse events and surgical complication. Biopsies and plasma pre-neoadjuvant therapy were collected and performed with whole-exome sequencing (WES), and ctDNA sequencing, respectively. Results: 27 patients were screened, of whom 25 patients were enrolled. All patients have completed the TNT. After neoadjuvant treatment, 21 patients underwent TME surgery. 7 (33.3%) patients were pCR, 3 (14.3%) achieved clinical complete or near complete response and 7 (33.3%) had a major pathological response. No progressive disease was found. WES and ctDNA sequencing analysis showed that tumor mutation burden (TMB) and level of ctDNA did not differ significantly between responders and non-responders. However, 3 responders with TMB high were found to be defective in other DNA damage repair pathways. Conclusions: Total neoadjuvant chemoradiation combined with neoadjuvant PD-1 blockade can achieve high pathological response rate, demonstrating its antitumor efficacy in pMMR locally advanced rectal cancer patients with high risk factors.
Phase II trial of perioperative chemotherapy of esophageal cancer: PIECE trial.
Authors: Motoo Nomura, Masahiro Goto, Masayuki Watanabe, Shinji Hato, Ken Kato, Eishi Baba, Hisahiro Matsubara, Hidenori Mukaida, Takako Yoshii, Masahiro Tsuda, Yasuhiro Tsubosa, Yuko Kitagawa, Ishikawa Hideki, Manabu Muto
Journal: Journal of Clinical Oncology (2022)

4038 Background: Neoadjuvant chemotherapy followed by surgery (NAC-S) is the standard therapy for locally advanced esophageal squamous cell cancer (ESCC) in Japan. The aim of this phase II trial was to assess the efficacy and safety of the addition of adjuvant S-1 after R0 resection in patients treated with NAC-S. Methods: Key eligibility criteria were as follows: ESCC of clinical stage IB-III (without T4 disease); aged 20 to 75 years; ECOG performance status 0 or 1; and performed neoadjuvant chemotherapy (5-FU + cisplatin). All patients registered before surgery. Patients received adjuvant therapy with 4 cycles of S-1 (80 mg/m 2 /day) that is administered orally for 4 weeks of a 6-weeks cycle. The primary endpoint was three-year relapse free survival (RFS). Results: A total of 52 patients were enrolled between January 2016 and January 2019. Two patients (one with small cell carcinoma and the other with synchronous malignancy) were excluded from analysis. Five patients were diagnosed as R1 or R2. Seven patients did not receive adjuvant S-1 due to adverse events of surgery in 5 patients, refusal to adjuvant S-1 in a patient, and forgot to start in a patient. Thirty-eight patients received adjuvant S-1, with 32 patients completing 4 cycles. The median relative dose intensity of adjuvant S-1 was 85.8%. Median follow-up time among survivors after surgery was 4.5 years (range 0.2-5.6). Three-year RFS in intention to treat population was 72.3% (90% confidence interval [CI] 59.9-81.5), suggesting that the primary endpoint was met, and 3-year overall survival was 85.0% (90% CI 73.9-91.6). Grade 3 or higher adverse event with an incidence 10% of greater were neutropenia (13.2%), anorexia (13.2%), and diarrhea (10.5%). There was no treatment-related death. Conclusions: Adjuvant S-1 showed promising efficacy with manageable safety profile for patients with resectable ESCC after NAC-S, and warrants further evaluation in larger studies. Clinical trial information: UMIN000020204.
Phase 2 study of trastuzumab deruxtecan in the neoadjuvant treatment for patients with HER2-positive gastric and gastroesophageal junction adenocarcinoma (EPOC2003).
Authors: Daisuke Takahari, Akihito Kawazoe, Nozomu Machida, Keiko Minashi, Yukinori Yamagata, Hiroki Hara, Masashi Wakabayashi, Yu Komura, Akihiro Sato, Takeshi Kuwata, Motohiro Kojima, Kohei Shitara
Journal: Journal of Clinical Oncology (2022)

TPS4161 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. DESTINY-Gastric01 study showed significantly higher objective response rate with T-DXd than physician's choice of chemotherapy (51.3%, vs. 14.3%, Shitara K, et al. NEJM 2020) as well as prolonged overall survival (median 12.5 vs. 8.4 months, hazard ratio 0.59). Considering that high response rate or major pathological response (MPR), which is defined as the proportion of subjects with &lt; 10% residual tumor may be associated with favorable survival outcomes after preoperative chemotherapy, T-DXd could be a promising neoadjuvant treatment for patients with gastric and gastroesophageal junction (GEJ) cancer. However, to our knowledge, there is no currently ongoing study of T-DXd as a neoadjuvant setting for patients with gastric and GEJ cancers. Methods: This is an open-label, single-arm, multicenter, investigator initiated phase 2 trial to evaluate antitumor activity of T-DXd as the neoadjuvant treatment for patients with HER2 positive gastric and GEJ adenocarcinoma. Eligible patients should have previously untreated locally advanced gastric and GEJ adenocarcinoma with clinical stage of T2-4 and/or N+ without distant metastasis. The main cohort will enroll patients with HER2 overexpression defined as immunohistochemistry （IHC）3+ or IHC2+/ in situ hybridization（ISH）+ by local assessment. According to the results of exploratory biomarker analysis of DESTINY-Gastric01 study (Shitara K, et al. ESMO-GI2021), patients with HER2-low expression (IHC1+ or 2+ with ISH negative) with HER2-extra cellular domein (ECD) higher than 11.6 ng/ml also will be enrolled into the exploratory cohort. Patients will receive 3 cycles of T-DXd (6.4mg/kg) by intravenous infusion every 3 weeks followed by surgery at 3 to 8 weeks after last T-DXd infusion.The primary endpoint is MPR rate. The threshold in the main cohort is defined as 20%, and the expected MPR rate was set at 45%. The minimum sample size of this trial is 23 patients in the main cohort (α- and β-error probabilities, 0.1 and 0.15, respectively). Total number of patients will be increased up to 27 patients depending on the enrollment. In addition, 10 patients will be recruited into the exploratory cohort. Secondary endpoints are pathologic complete response (pCR) rate, curative resection rate, and adverse event rate. Biomarker analyses including whole exome sequencing, RNA sequencing, proteomics, and ctDNA changes will also be conducted using pre- and post-treatment tumor and blood samples. Enrollment is ongoing at six sites in Japan from November 2021. Clinical trial information: NCT05034887.
Safety and efficacy of MORAb-202 in patients (pts) with platinum-resistant ovarian cancer (PROC): Results from the expansion part of a phase 1 trial.
Authors: Shin Nishio, Mayu Yunokawa, Koji Matsumoto, Kazuhiro Takehara, Kosei Hasegawa, Yasuyuki Hirashima, Hidenori Kato, Hiroki Ikezawa, Maiko Nomoto, Seiichi Hayato, Yohei Otake, Takuma Miura, Kan Yonemori
Journal: Journal of Clinical Oncology (2022)

5513 Background: MORAb-202 is an antibody-drug conjugate consisting of farletuzumab (an antibody that binds to folate receptor alpha [FRα]) paired with eribulin mesylate (a microtubule dynamics inhibitor) conjugated via a cathepsin-B–cleavable linker. The dose-escalation part of this phase 1 study confirmed antitumor activity in pts with ovarian cancer (Shimizu 2021, CCR); based on efficacy and safety, MORAb-202 0.9 mg/kg and 1.2 mg/kg Q3W were chosen as doses for the expansion part of this study in pts with PROC. Methods: The primary objective for the expansion part of this phase 1 study conducted in Japan was to define the safety and tolerability of MORAb-202. Secondary objectives included PK characterization and efficacy assessment (best overall response, objective response rate, progression-free survival, and overall survival). Eligible pts included those who had received ≤2 regimens of chemotherapy after diagnosis of PROC, had measurable disease per RECIST v1.1, and an ECOG PS of ≤1. Pts (except those with high grade serous histology) in the expansion phase were required to be FRα positive. The expansion phase began at the 0.9 mg/kg dose (Cohort 1); Cohort 2 (1.2 mg/kg) was initiated after safety assessment of Cohort 1 was completed. Tumor responses were assessed per RECIST v1.1 by investigator. Results: Twenty-four pts were treated in Cohort 1 and 21 pts were treated in Cohort 2. Grade ≥3 TEAEs occurred in 33.3% of pts in Cohort 1 and 28.6% of pts in Cohort 2. The most common TEAE was interstitial lung disease (ILD)/pneumonitis at both dose levels (Cohort 1: 37.5% [n=9; 8 with grade 1, 1 with grade 2]; Cohort 2: 66.7% [n=14; 6 with grade 1, 7 with grade 2, 1 with grade 3]). Other common TEAEs of any grade were nausea (25.0%; 33.3%), pyrexia (33.3%; 42.9%), malaise (16.7%; 28.6%), and headache (12.5%; 47.6%), in Cohorts 1 and 2, respectively. ORR was 25.0% and 52.4% in Cohorts 1 and 2, respectively (Table). Antitumor activity was observed across FRα-expression levels (&lt;50% and ≥50%) and will be presented. Conclusions: In the PROC population, antitumor activity was seen with both the MORAb-202 0.9 mg/kg and 1.2 mg/kg doses. While pt numbers were small, efficacy was observed irrespective of FRα-expression levels. ILD/pneumonitis was the most common TEAE and was low grade in most pts. Dose optimization is ongoing to maximize the benefit/risk profile of MORAb-202. Clinical trial information: NCT03386942. [Table: see text]
Landscape of homologous recombination reversion mutations in gynecologic malignancies.
Authors: Susan M. Domchek, Kim Anna Reiss, Kate Nathanson, Shannon Bailey, Natalie Danziger, James Thornton, Mark Hartman, Chenming Cui, Lei Yang, Matthew Margolis, Erica Gornstein, Ethan Sokol, Douglas I. Lin, Alexa Betzig Schrock, Douglas A Mata, Christine Vietz, Jeffrey S. Ross, Geoffrey R. Oxnard, Julia Andrea Elvin, Brennan James Decker
Journal: Journal of Clinical Oncology (2022)

5576 Background: Homologous recombination (HR) reversion mutations (REV) are biomarkers for predicting resistance to platinum and PARP inhibitor therapies. The biologic diversity of REV represents a diagnostic challenge. An automated computational approach was used to detect REV for analysis of genomic features of REV-positive ovarian epithelial, fallopian tube, and peritoneal cancers. Methods: Retrospective study of tissue (n = 23,612) and liquid biopsy (n = 869) samples from patients undergoing hybrid-capture comprehensive genomic profiling during routine clinical care 11/2012-03/2021. A proprietary algorithm tested for seven distinct REV mechanisms in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D. For subjects with multiple samples, the earliest REV-positive sample was used for downstream analyses. Results: Among 23,866 ovarian epithelial, fallopian tube, and peritoneal cancers, 16.4% (n = 3,920) had at least one pathogenic variant (PV) in BRCA1 (10%, n = 2,383), BRCA2 (5.5%, n = 1,320), PALB2 (0.67%, n = 160), RAD51C (0.64%, n = 152), or RAD51D (0.47%, n = 113). 3.9% (154/3,920) of patients with one or more PV had REV. REV were found in tumors with PV in BRCA2 at twice the frequency of BRCA1 (6.0%, [79/1,320] vs 3.0% [71/2,383]; p &lt; 0.001). REV involving RAD51D (1.8%, 2/113), RAD51C (0.7%, 1/152), or PALB2 (0.6%, 1/160) were rarer. A total of 193 REV pairs were identified. The most frequent REV mechanism was an exonic non-frameshift deletion completely encompassing a PV (45%, 87/193). Other recurrent mechanisms included restoration of the reading frame of a frameshift PV (21%, 42/193), replacement of a PV with a benign missense substitution at the same codon (16%, 32/193), and deletion with intronic breakpoints encompassing a PV (15%, 29/193). REV were significantly more prevalent in liquid biopsies than in tissue samples with PV (16% [20/124] vs. 3.5% [134/3,796]; p &lt; 0.001). A range of 1-6 REV pairs were found per sample (liquid: 1-6, tissue: 1-3). Multiple REV per sample was more common in liquid biopsies (35% [7/20] vs. 11% [15/134]; p = 0.011). These differences likely reflect stage of disease and sampling of multiple subclones. Conclusions: BRCA2 PV are most frequently reverted in gynecologic tumors. REV are also common in tumors with BRCA1 PV and can more rarely occur in other HR genes. Liquid biopsy is enriched for detection of polyclonal resistance. Diverse REV mechanisms highlight a need for robust detection to incorporate REV in identifying treatment resistance and guiding downstream therapy selection.
T-cell receptor repertoire analysis based on RNA sequencing data from tumor cells and tumor-infiltrating lymphocytes.
Authors: Cheng Du, Lili Cui, Meiling Wang, Long Li, Zhendong Zheng, Danni Liu, Yingmei Li, Tianhao Mu
Journal: Journal of Clinical Oncology (2022)

3058 Background: T-cell receptor (TCR) repertoire has been thought to be indicative in cancer progression and treatment response. Previous methods mainly focused on peripheral blood or fresh tumor tissue, which were sometimes logistically limited in clinical settings. Tumor-infiltrating lymphocytes (TILs), which harbored TCR characteristics, were also mingled with tumor cells (TCs), which brought hurdles in extracting TCR signals from bulk RNA sequencing data. Here we employed a set of RNA sequencing data from paired FFPE tumor samples and their micro-dissected TILs, to analyze and compare the TCR features in tumor cells and TILs. Methods: RNA sequencing data of 14 tumor cell samples and matched TILs were downloaded from NCBI-SRA (accession: PRJEB36554). Raw data were cleaned up by Trim Galore (v0.6.2). TCR clonotypes were assembled and quantified from clean fastq files by MiXCR (v3.0.4). Diversity and clonality metrics were analyzed using VDJtools (v1.2.1) and in-house Pearl scripts. Results: The median mapping rates of sequencing reads to TCR regions were 0.29% and 1.80% for TCs and TILs respectively (p = 0.00051). TCR diversity of TCs and TILs was characterized by Shannon and Simpson index respectively. The median Shannon index was 1.889 and 2.694 in TCs and TILs (p = 0.00034, unpaired Wilcoxon rank-sum test); the median Simpson index was 0.8724 and 0.9420 in TCs and TILs (p = 0.0058). Conclusions: RNA isolated from clinical FFPE samples could be used for TCR analysis. Micro-dissection of TILs could enhance TCR signals of unprocessed tumor tissues.
Nivolumab in squamous cell carcinomas of the head and neck (SCCHN): A real-world outcome study in Ontario, Canada.
Authors: Arman Zereshkian, Ruaa Shafi, Gregory Russell Pond, Sebastien J. Hotte
Journal: Journal of Clinical Oncology (2022)

e18017 Background: The CheckMate-141 trial led to the approval of nivolumab in platinum-resistant metastatic squamous cell carcinomas of the head and neck (SCCHN). We evaluated outcomes of SCCHN patients in Ontario, Canada treated with nivolumab since its funding through the New Drug Funding Program (NDFP) of Cancer Care Ontario (CCO). Methods: Retrospective review using the provincial treatment registry (CCO NDFP) was undertaken. Patient characteristics, reason for treatment, treatment length, and date of death were collected. Kaplan-Meier method was used to estimate overall survival and Cox regression to evaluate prognostic effect of selected factors. Results: 134 patients with SCCHN received nivolumab between March 2017 and March 2019. Median patient age was 63 years with 80.6% male. Nivolumab was used as second-line therapy after disease relapse within 6 months of curative-intent platinum chemotherapy (PC) in 39.6% of patients (Indication 1 – I1), used as second-line therapy post PC in non-curative intent in 42.6% of patients (Indication 2 – I2), and used as first-line therapy in non-curative intent due to contraindication for PC in 17.2% of patients (Indication 3 – I3). Median overall survival (mOS) was 5.8 months (95% confidence intervals (CI) 4.5-7.3), and one-year OS was 28.4% (CI 2.10-36.1). HPV status had no statistically significant impact on OS (p = 0.12). Patients with a lower BSA (&lt; 1.81) had median OS of 3.9 months (CI 3.1-6.7) versus 9.0 months (CI 6.5-14.8) in those with higher BSA, HR = 0.12 (CI 0.04-0.39, p &lt; 0.001). Differences between indications was statistically significant (p &lt; 0.001). Patients who received nivolumab for I1 had mOS 7.2 months (CI 3.8-9.8) versus 11.9 months (CI 6.2-not reached) for I3, HR = 1.73(CI 0.94-3.16). Patients who received nivolumab for I2 had mOS 3.9 months (CI 2.9-5.4) as compared to I3, HR = 3.27(CI 1.80-5.94). Patients who received nivolumab for I2 had poorer mOS as compared to I1 HR = 1.90(CI 1.23-2.92). Conclusions: Real world data in Ontario demonstrates poorer mOS, but similar 1-year survival compared to CheckMate-141 trial. HPV status had no significant impact on mOS. Patients who received nivolumab as first-line therapy in the non-curative setting appeared to have longer mOS than those who received initial PC for non-curative intent followed by nivolumab. Patients who received nivolumab as second-line therapy post PC in non-curative intent setting as compared to within 6 months of curative-intent therapy had poorer mOS.